Progressive Multifocal Leukoencephalopathy (PML) is a deadly opportunistic infection of the brain caused by the polyomavirus JC (JCV), which occurs in immunosuppressed individuals. There is no treatment for PML, and the incidence of this disease has not decreased significantly in HIV+ patients since the availability of highly active antiretroviral therapy (HAART). In addition, a growing number of organ transplant recipients are also at risk for PML. Cellular immunity against JCV has been associated with a favorable outcome of PML. Therefore, the development of strategies aiming at enhancing JCV-specific cellular immune response in immunosuppressed PML patients is urgently needed. Dendritic cells (DC) are the professional antigen presenting cells in the body and have a key role in the presentation of viral or tumor peptides to cytotoxic T lymphocytes (CTL). Therefore, injection of autologous DC pulsed with viral or tumor peptides has been used in humans for therapeutic purposes. However, prior studies need to be performed to determine if such dendritic cell-based immunotherapy can be a viable option for PML. We have observed that only a subgroup of PML patients had detectable JCV-specific CTL, and became PML survivors. Understanding if genetic factors can differentiate these individuals from those who fail to mount such an immune response is of primary importance. We hypothesize that host factors such as the MHC class I genotype of the patients play a major role in their ability to recognize and destroy JCV-infected cells. In addition, the degree of differentiation of JCV-specific CTL in blood and CSF, and the breath of their repertoire in a given individual may be critical for the containment of JCV. Such knowledge will be of central importance for devising appropriate immunotherapies for PML. To test these hypotheses, we propose to perform the following experiments: 1) Determine the role of HLA class I alleles in PML outcome; 2) Characterize the phenotype of JCV-specific CTL; 3) Analyze the repertoire of JCV-specific CTL in blood and CSF; 4) Perform preclinical studies of dendritic cell-based immunotherapy for PML.